This invention relates to the use of a therapeutic combination of two compounds to treat pain. The method of pain treatment comprises co-administration of an azapirone with acetaminophen (paracetamol). This combination of agents produces a more robust opioid-type analgesia providing more rapid onset and/or longer duration.
Acetaminophen is an established analgesic agent having only weak anti-inflammatory activity and can be classified as a non-NSAID analgesic. Ibuprofen is an example of a non-steroidal analgesic having significant anti-inflammatory properties and is classified as a non-steroidal anti-inflammatory drug (NSAID). Acetaminophen is believed to relieve pain by elevation of the pain threshold and is generally given in amounts ranging from about 600 to 1300 mg per dose in humans.
While acetaminophen is equally effective as aspirin, it is unlikely to produce many of the adverse effects of aspirin and aspirin-containing products. Acetaminophen itself, however, has been associated with a propensity for contributing to liver damage in patients that ingest significant amounts of alcohol. The dose-related toxic effect of acetaminophen on liver is demonstrated by the hepatic toxicity seen with overdosage of acetaminophen. Therefore, it would be desirable to be able to effectively treat pain utilizing lower doses of acetaminophen.
Combinations of various analgesics to provide additive effects in treating pain are known in the literature; e.g., combinations of aspirin with codeine or other narcotic analgesics are known to provide additive analgesic effects in man. See: The Pharmacologic Basis of Therapeutics, 5th edition, Macmillan Publishing Co., 1975, pp. 325-358. More active analgesic combinations are continually sought since they may be able to relieve pain with reduced dosages, thereby diminishing accompanying adverse effects and toxicities resulting from higher dosages. It is particularly desirable to discover a potentiating agent and/or a synergistic combination effect. The present invention concerns the concurrent administration of an azapirone with acetaminophen to provide increased analgesic effects.
Acetaminophen combinations have been previously disclosed.
Cooper, in U.S. Pat. No. 4,794,112 disclosed combinations of hydroxyzine with acetaminophen as being effective analgesic compositions.
Certain azapirone compounds and their pharmaceutically acceptable salts have been described as being useful in treating anxiety and depression disorders. These compounds have general structure (I) and are identified below.
These particular azapirones contain the pyrimidinylpiperazine moiety as an integral part of their molecular structure. The most studied and well-known member of this compound class is buspirone.
Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is a pharmaceutically active compound which was disclosed in U.S. Pat. No. 4,182,763 as being effective for the treatment of anxiety mixed with depression. A number of other pharmacologic actions useful in treating various clinical disorders have been reported for buspirone. Antinociceptive effects of buspirone have been described in numerous references. For example, Giordano, et al., 1989, Pain, 39, 109-113, suggest the potential use of buspirone in treating pain arising from chemical and mechanical nociception.
Additional study of buspirone-induced antinociception by Giordano et al., 1992, Pain, 50, 365-372, concluded that buspirone produced a non-opioid type of analgesia.
Roberts, et al., in GB 2,222,768 disclose and claim the use of 5-HT1-like agonists as analgesics. A group of specifically disclosed agents classified as agonists, including buspirone, were reported as being expected to exhibit analgesic activity to a greater or lesser extent than the 5-HT1 agonist 8-hydroxy-DPAT.
A study on neuropathic pain by Kishare-Kumar, et al., reported in Pain, 1989, 37, 223-227, indicated that acute high doses of buspirone did not relieve neuropathic pain.
Combining buspirone with other analgesic has been disclosed by B. -J. Cao, et al., in J. Pharm. Pharmacol., 1994, 46, 331-332, where buspirone was demonstrated as acting to attenuate xylazine-induced antinociception. These studies were prompted by the earlier reports of buspirone""s attenuation of antinociception induced by morphine and sufentanil. These reports teach away from the use of buspirone to potentiate the analgesic effect of another pain-relieving agent.
Plachetka in U.S. Pat. No. 5,872,145 discloses a method of treating migraine by the co-timely administration of a 5-HT agonist and a NSAID or non-NSAID analgesic agent. While acetaminophen is listed as an example of such a non-NSAID, buspirone is not mentioned in the patent. The intended 5-HT1 agonist prototype is sumatriptan, a member of a different 5-HT1 subclass than buspirone.
Buspirone, by itself, has been reported to be useful in the preventive treatment of headaches. Cf: Pascual, et al., Acta. Neurol. Scand., 1998, 97, 142.
Buspirone is commercially available from Bristol-Myers Squibb Company for the treatment of anxiety. Use in pain management is not an approved indication for buspirone.
In summary, the prior art does not disclose or suggest the novel use of an azapirone such as buspirone to strengthen the analgesic effect of acetaminophen. The concurrent administration of an azapirone such as buspirone with acetaminophen provides a qualitative improvement in the resulting analgesia. In the case of buspirone, the onset, duration and degree of analgesia produced is morphine-like and as such is unexpected, particularly in view of reports of buspirone""s attenuation of the antinociceptic effects of certain analgesics.
The present invention provides a method for treatment of pain comprising the concurrent administration of azapirones such as buspirone and acetaminophen in a manner which results in strengthening of the antinociceptive effects of acetaminophen. The analgesia produced by the concurrent administration of acetaminophen and azapirones such as buspirone is qualitatively opioid-like, resembling morphine in having a rapid onset, providing greater pain relief and maintaining the analgesic effect for a longer time. The addition of an azapirone such as buspirone also allows for the use of smaller amounts of acetaminophen, thereby reducing the liver toxicity potential. The present invention also comprises pharmaceutical compositions and pharmaceutical kit/packaging containing acetaminophen and an azapirone such as buspirone for combination therapy.